ABSTRACT Pediatric recurrent respiratory papillomatosis (RRP), characterized by papillomas of the aerodigestive tract, is usually caused by low risk types 6 and 11 of the human papilloma virus (HPV). Although it is the most common benign neoplasm of the larynx in children, disease risk and progression are poorly understood. The clinical course of RRP poses a severe burden as it is unpredictable and carries a risk of malignant conversion when it progresses to other sites in the aerodigestive tract. A diagnosis before the age of 3 has a higher likelihood of both requiring more than 4 surgical procedures per year and having more than one affected anatomic site, underscoring the frequent need for adjuvant therapy in the pediatric population. Furthermore, many patients require additional medical therapies including Interferon-?, Cidifovir, and Ribavirin due to the difficulty in treating this disease with surgical resection alone. Despite the use of an array of these medical therapies, no single agent has been effective at eliminating pediatric RRP, and we cannot predict which patients will respond to any particular drug or treatment regimen. Donor predisposition and HPV viral biology likely underlie limited disease susceptibility to these adjuvant therapies. Clinical progress in the RRP field has been hindered by the absence of authentic model systems to define predictive biomarkers and key regulators of RRP development. Primary monolayer RRP cells from adults, but not children, are reported in the literature. However, monolayer culture is not conducive to the study of the HPV life cycle as this requires 3D differentiated mucosa. Using fresh tumor and matched normal tissue from 8 individuals, we have established a pipeline of internally controlled, patient-specific models of RRP. These have been successfully engineered into organotypic epithelial rafts for studies of the differentiated environment and viral life cycle. Preliminary genomic, transcriptomic, and molecular studies support the feasibility of using these models for the proposed translational studies to identify disease biomarkers, molecular targets, and clinically relevant drugs. This research is carried out by a team of scientists with a history of collaboration and complementery expertise in epithelial models, omics methodologies, statistics and pathology, and clinicians who care for one of the largest cohort of children and young adults with RRP in the USA,